The risk profiles of pregnancy-related cerebral venous thrombosis: a retrospective study in a comprehensive hospital.

OBJECTIVES: To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT). METHODS: A retrospective cohort of 16 patients diagnosed with CVT during pregnancy and postpartum (within six weeks after delivery) in a comprehensive hospital in China between 2009 and 2022 were carefully reviewed, focusing on demographic, clinical, and etiological characteristics, especially underlying causes. We matched 16 PCVT patients with 64 pregnant and puerperal women without PCVT to explore risk factors and clinical susceptibility to PCVT. RESULTS: PCVT occurred commonly during the first trimester (43.75%) and the puerperium (37.5%). The frequency of anemia, thrombocytosis and thrombocytopenia during pregnancy, dehydration, and pre-pregnancy anemia was significantly higher in women with PCVT than in those without PCVT (P < 0.05). Among the 16 patients, five were diagnosed with antiphospholipid syndrome and one was diagnosed with systemic lupus erythematosus. Three patients had distinct protein S deficiency and one had protein C deficiency. Whole Exome Sequencing (WES) was performed for five patients and revealed likely pathogenic mutations associated with CVT, including heterozygous PROC c.1218G > A (p. Met406Ile), heterozygous PROS1 c.301C > T (p. Arg101Cys), composite heterozygous mutation in the F8 gene (c.144-1259C > T; c.6724G > A (p. Val2242Met)) and homozygous MTHFR c.677C > T (p. Ala222Val). CONCLUSIONS: The occurrence of anemia, thrombocytopenia and thrombocytosis during pregnancy, dehydration and pre-pregnancy anemia suggested a greater susceptibility to PCVT. For confirmed PCVT patients, autoimmune diseases, hereditary thrombophilia, and hematological disorders were common causes. Screening for potential etiologies should be paid more attention, as it has implications for treatment and long-term management.

Genotypes and phenotypes of protein S deficiency in Thai children with thromboembolism.

The prevalence of protein S (PS) deficiency in Asian patients with venous thromboembolism is around 8-30%, higher than that in Caucasian populations. The present study reports the genotypes (including one novel mutation) and phenotypes of children with PS deficiency at a tertiary care institute. A total of six patients were included, three with arterial ischemic stroke, two with cerebral venous sinus thrombosis, and one with deep vein thrombosis. PS mutations were identified in four patients: p.R355C, p.G336D, p.E67A, and p.N188KfsX9. p.N188KfsX9 is a novel mutation with less than 20% PS activity noted in heterozygotes.

Genetic Risk Factors in Venous Thromboembolism.

Genetic risk factors predispose to thrombophilia and play the most important etiopathogenic role in venous thromboembolism (VTE) in people younger than 50 years old. At least one inherited risk factor could be found in about half of the cases with a first episode of idiopathic VTE.Roughly, genetic risk factors are classified into two main categories: loss of function mutations (such as deficiencies of antithrombin, protein C, protein S) and gain of function mutations, (such as prothrombin mutation G20210A, factor V Leiden). A revolutionary contribution to the genetic background of VTE was brought by the achievements of the genome-wide association studies which analyze the association of a huge number of polymorphisms in large sample size.Hereditary thrombophilia testing should be done only in selected cases. The detection of hereditary thrombophilia has impact on the management of the anticoagulation in children with purpura fulminans, pregnant women at risk of VTE and may be useful in the assessment of the risk for recurrent thrombosis in patients presenting an episode of VTE at a young age (<40 years) and in cases with positive family history regarding thrombosis.

Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism.

BACKGROUND: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation. METHODS: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis. RESULTS: Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0-2 y, 45%), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75%), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism. CONCLUSION: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

Protein S deficiency complicated pregnancy in women with recurrent pregnancy loss.

This prospective study aimed to evaluate pregnancy outcome and complications in women with recurrent pregnancy loss (RPL) and protein S (PS) deficiency, who received low dose aspirin (LDA) or LDA plus heparin (LDA/H) therapies. Clinical characteristics, pregnancy outcome and complications of 38 women with two or more RPL and <60% of plasma free PS antigen were compared among three groups: antiphospholipid antibody (aPL)-negative women who received LDA (group A), aPL-negative women who received LDA/H (group B) and aPL-positive women who received LDA/H (group C). Gestational weeks (GW) at delivery in group C (median 32 GW) were earlier than 40 GW in group A and 38.5 GW in group B (p < 0.05). The birth weight in group C (median 1794 g) was less than 2855 g in group B (p < 0.05). The incidences of fetal growth restriction (37.5%), pregnancy-induced hypertension (37.5%), and preterm delivery (62.5%) in group C were higher than those (4.5%, 0%, and 4.5%, respectively) in group B (p<0.05). Women with RPL, PS deficiency, and positive aPL had high risks for adverse pregnancy outcome and complications, even when they received LDA/H therapy. Among women with RPL, PS, and negative aPL, there was no difference in these risks between LDA alone and LDA/H therapies.

Skin necrosis: a rare complication of protein S deficiency.

Hereditary protein S deficiency is an autosomal dominant disorder leading to recurrent venous thrombosis and, less commonly, to arterial thrombosis. Cases of skin necrosis have been documented in patients with protein C or S deficiency while being treated with warfarin. We describe herein a patient with protein S deficiency who developed significant skin necrosis without being exposed to warfarin. She had a protracted clinical course resulting in gangrene and transmetatarsal amputation. Recognition of this rare complication and an earlyhematology referral may prevent dismal outcomes in patients with protein S deficiency.

Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry.

Thrombophilia is a well-established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43 years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20 years and younger to 21·9% in patients over the age of 70 years; P < 0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk-associated VTE (57·7% vs. 47·7%; P = 0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.

Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies.

BACKGROUND AND AIM: The prevalence of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiencies in portal vein system thrombosis (PVST) and Budd-Chiari syndrome (BCS) are substantially varied in different studies. No quantitative syntheses of these studies have been performed. A systematic review and meta-analysis were conducted to examine the prevalence of inherited AT, PC, and PS deficiencies in these patients and to compare the prevalence with healthy subjects. METHODS: PubMed, EMBASE, and Cochrane Library databases were employed to identify all studies in which inherited AT, PC, and PS deficiencies in PVST and/or BCS were evaluated by family study or gene analysis. Prevalence and odds ratios of these inherited deficiencies were pooled; heterogeneity among studies was evaluated. RESULTS: Nine studies were included in our meta-analysis. The pooled prevalence of inherited AT, PC, and PS deficiencies were 3.9%, 5.6%, and 2.6% in PVST, and 2.3%, 3.8%, and 3.0% in BCS, respectively. Heterogeneity among studies was not significant except for the analysis of inherited PC deficiency in BCS. Three studies compared the prevalence of these inherited deficiencies between PVST patients and healthy subjects. The pooled odds ratios of inherited AT, PC, and PS deficiencies for PVST patients were 8.89 (95% confidence interval [CI] 2.34-33.72, P = 0.0011), 17.63 (95% CI 1.97-158.21, P = 0.0032), and 8.00 (95% CI 1.61-39.86, P = 0.011), respectively. Only one study demonstrated that no inherited deficiency was found in both BCS patients and healthy subjects. CONCLUSIONS: Inherited AT, PC, and PS deficiencies are rare in PVST and BCS. These inherited deficiencies increase the risk of PVST.

Superficial vein thrombosis in patients with varicose veins: role of thrombophilia factors, age and body mass.

OBJECTIVES: To investigate the association of various risk factors including thrombophilia defects, in patients with varicose veins (VVs) and history of episodes of superficial vein thrombosis (SVT). MATERIALS AND METHODS: Two hundred and thirty patients with primary VVs were included in this prospective study. A total of 128 (43 men, age 56 ± 13) had an acute episode or a previous history of SVT, while 102 patients (27 men, age 48 ± 12) did not. Coagulation profile investigation included serum levels of protein C (PC), protein S (PS), anti-thrombin III (AT III), plasminogen (Plg), A(2) antiplasmin (A(2)Apl) and activated protein C resistance (APCR). This was performed at least 3 months after the SVT episode to ensure that the results were not altered. Age and body mass index (BMI) were also assessed. RESULTS: PC deficiency was detected in 3/128 (2.3%), PS deficiency in 19/128 (14.8%), AT III deficiency in 29/128 (22.7%), Plg deficiency in 9/128 (7%), A(2)Apl excess in 3/128 (2.3%) and APCR in 9/128 (7%) patients with SVT and 0/102 (0%), 3/102 (2.9%), 15/102 (14.7%), 6/102 (5.8%), 0/102 (0%) and 1/102 (0.9%) in the control group, respectively. BMI greater than 30 kg m(-2) was associated with SVT. In logistic regression analysis SVT was associated with PS deficiency (odds ratio (OR) 6.7, p = 0.004, 95% confidence interval (CI) 1.83-24.53), obesity (OR 3.5, p = 0.003, 95% CI 1.53-8.05) and age (OR 1.038, p = 0.001, 95% CI 1.01-1.06). CONCLUSIONS: Obesity, age and PS deficiency were found as factors associated with SVT episodes in patients with VVs.

Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss.

PURPOSE: To evaluate the prevalence of thrombophilic disorders in polycystic ovarian syndrome (PCOS) women with history of recurrent pregnancy loss (RPL). MATERIALS AND METHODS: This study was carried out in 184 women with history of RPL, of which 92 of them were diagnosed with PCOS and 92 patients were without known PCOS. The prevalence of thrombophilic disorders was compared between the two mentioned groups. RESULTS: According to the findings, 70.7% of PCOS women with history of RPL had thrombophilic disorders. The prevalence of protein C deficiency was significantly higher in PCOS group compared to the non-PCOS group (21.7% vs. 10.9%, p = 0.04). There was a trend toward higher prevalence of protein S deficiency in PCOS group compared to the control group, but the difference did not reach statistical significance (23.9% vs. 13%, p = 0.05). The prevalence of other thrombophilic disorders such as antithrombin III deficiency, homocysteine elevation, antiphospholipid antibody and Factor V Leiden was comparable between groups. CONCLUSION: The prevalence of thrombophilic disorders was more common in PCOS women than the normal group. The protein C deficiency is associated with PCOS in women with history of RPL. There was a trend toward higher prevalence of protein S deficiency in PCOS women, which needs further study.

Thrombophilia among Chinese women with venous thromboembolism during pregnancy.

AIMS: To assess the prevalence of thrombophilia among Chinese women with venous thromboembolism (VTE) developed during pregnancy. METHODS: Based on information from a tertiary teaching unit, all recorded cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) during pregnancy diagnosed between 1997 and 2005, were assessed for prevalence of thrombophilia. Fifty-five healthy women, who had at least one normal pregnancy but without any previous history of VTE, were recruited as controls. RESULTS: A total of 44 subjects completed thrombophilia screening, of whom 5 (11%) were confirmed to have thrombophilia [protein C (PC) deficiency (2), protein S (PS) deficiency (1), combined PC & PS deficiency (1) and antithrombin III deficiency (1)]. Homozygous 5,10-methylenetetrahydrofolate reductase (C677T) gene mutation was found in 6 (14%) subjects but not in the controls. There was no antiphospholipid syndrome, activated PC resistance, factor V Leiden or prothrombin gene mutations. CONCLUSION: In the Chinese population, PS and PC deficiencies are common thrombophilia for VTE during pregnancy and thrombophilia screening should be recommended in all pregnant women who suffer from VTE.

Thrombophilia in childhood: to test or not to test.

Inherited thrombophilia is defined as a genetically determined tendency to develop venous thromboembolism. In children, inherited thrombophilia contributes to the development of pediatric thromboembolic disease. As a consequence, pediatric hematologists are increasingly requested to test thrombophilia in pediatric patients with thrombosis or asymptomatic children from thrombophilic families. This article reviews the benefits and limitations of testing for thrombophilic disorders, for example, factor V Leiden, prothrombin mutation, and deficiencies of antithrombin, protein C, or protein S in childhood.

Protein C and/or protein S deficiency and occurrence of stent thrombosis: a hitherto unrecognized association.

OBJECTIVE: To study the prevalence of protein C and/or protein S deficiency in patients of stent thrombosis and correlate its association with the event, if any. BACKGROUND: Stent thrombosis is the Achilles heel of percutaneous coronary intervention (PCI) and has been associated with so many predisposing factors that if one analyzes all patients undergoing PCI, one or more such factors would be present in almost every patient; however, its incidence remains no more than 1-2%. We hypothesized a preexisting prothrombotic state, or tendency, in a small proportion of patients that possibly plays a key role in its occurrence. METHODS: We analyzed the prothrombotic tendency of individual patients by studying protein C and protein S levels. Thirteen patients presenting with stent thrombosis and 24 age- and sex-matched controls were studied. RESULTS: Protein S was found to be deficient in 11 of 13 patients (84.6%) of stent thrombosis and in only 4 of 24 patients (16.7%) in matched controls (P < 0.001), while protein C was found deficient in 2 of 12 patients (16.7%) of stent thrombosis, and 1 of 24 patients (4.2%) in matched controls (P = 0.25) and either protein C or protein S was deficient in 11 of 13 (84.6%) of stent thrombosis and 5 of 24 (20.8%) controls (P = <0.001). Low protein S levels were strongly associated with stent thrombosis (odds ratio 3.04, 95% confidence interval 1.34-4.7) with sensitivity 0.73 and specificity of 0.91. CONCLUSIONS: Protein S deficiency is strongly correlated to the occurrence of stent thrombosis, a fact that has hitherto not been recognized and needs further evaluation.

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game.

Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play an important role in the regulation of blood coagulation as natural anticoagulants. PC is activated by thrombin and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V. The free form of PS is an important cofactor of APC. Deficiencies in these proteins lead to an increased risk of venous thromboembolism; a few reports have also associated these deficiencies with arterial diseases. The degree of risk and the prevalence of PC and PS deficiency among patients with thrombosis and in those in the general population have been examined by several population studies with conflicting results, primarily due to methodological variability. The molecular genetic background of PC and PS deficiencies is heterogeneous. Most of the mutations cause type I deficiency (quantitative disorder). Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases. The diagnosis of PC and PS deficiencies is challenging; functional tests are influenced by several pre-analytical and analytical factors, and the diagnosis using molecular genetics also has special difficulties. Large gene segment deletions often remain undetected by DNA sequencing methods. The presence of the PS pseudogene makes genetic diagnosis even more complicated.

High Prevalence of Acquired Thrombophilia Without Prognosis Value in Patients With Coronavirus Disease 2019.

Background Recent literature reports a strong thrombotic tendency in patients hospitalized for a coronavirus disease 2019 (COVID-19) infection. This characteristic is unusual and seems specific to COVID-19 infections, especially in their severe form. Viral infections can trigger acquired thrombophilia, which can then lead to thrombotic complications. We investigate for the presence of acquired thrombophilia, which could participate in this phenomenon, and report its prevalence. We also wonder if these thrombophilias participate in the bad prognosis of severe COVID-19 infections. Methods and Results In 89 consecutive patients hospitalized for COVID-19 infection, we found a 20% prevalence of PS (protein S) deficiency and a high (ie, 72%) prevalence of antiphospholipid antibodies: mainly lupus anticoagulant. The presence of PS deficiency or antiphospholipid antibodies was not linked with a prolonged activated partial thromboplastin time nor with D-dimer, fibrinogen, or CRP (C-reactive protein) concentrations. These coagulation abnormalities are also not linked with thrombotic clinical events occurring during hospitalization nor with mortality. Conclusions We assess a high prevalence of positive tests detecting thrombophilia in COVID-19 infections. However, in our series, these acquired thrombophilias are not correlated with the severity of the disease nor with the occurrence of thrombotic events. Albeit the strong thrombotic tendency in COVID-19 infections, the presence of frequent acquired thrombophilia may be part of the inflammation storm of COVID-19 and should not systematically modify our strategy on prophylactic anticoagulant treatment, which is already revised upwards in this pathological condition. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04335162.

Superficial venous thrombosis: role of inherited deficiency of natural anticoagulants in extension to deep veins.

AIM: Superficial venous thrombosis (SVT) has been considered for a long time a limited clinical condition of low importance, but this approach has changed in recent years, when several studies demonstrated that extension to deep veins occurs in 7.3 to 44% of patients, with high prevalence of pulmonary embolism. The aim of this study was to evaluate the prevalence of inherited deficiency of natural coagulation inhibitors in patients suffering from SVT in both normal and varicose veins, and to understand their role in extension to deep veins. METHODS: The study included 83 patients with SVT, without clinically obvious risk factors. Ultrasound examination was performed, and deficiencies of Protein C, Protein S and Antithrombin (AT) were investigated. RESULTS: In the patients where SVT occurred in normal veins, coagulation inhibitor deficiencies were 6.45% in the absence of extension and 62.5% in patients with extension to deep veins. In the patients with varicose vein SVT, the presence of these factors was less evident, but their prevalence was considerably higher in those with extension to deep veins (36.3%) than in non-extension (6.06%). CONCLUSIONS: Present data confirm the role of inherited thrombophilic states related to inhibitor deficiency, considering them as risk factors for SVT in normal veins. Furthermore, an association has been found between their presence and the progression of SVT to deep veins.

Acute thrombosis of abdominal aorta and hypercoagulable disorders.

Acute abdominal aortic occlusion (AAAO) is a rare, life threatening condition, which usually occurs in elderly patients, causing challenging management issues. In patients who have no cardiac or vascular disease this catastrophic event is very rare and is due to hypercoagulable disorders. This study reviews the literature on AAAO in hypercoagulable states in the light of our experience on a case of an acute thrombosis of nonaneurysmal, nonatherosclerotic abdominal aorta in a female patient with protein S deficiency and Sjögren's syndrome and her younger brother, which was found to have atherosclerotic involvement of distal aorta and elevation in homocysteine levels. Because of a misleading clinical presentation, the diagnosis was delayed and conservative treatment failed. Both were successfully treated with emergency aorto-bifemoral grafting. Other cases of arterial thrombosis and hypercoagulable disorders were found in first-degree relatives. Our experience and the review of the literature suggest that the interaction between host and environment factors can lead to acute thrombosis of the non-pathologic abdominal aorta; not only classic hypercoagulability disorders, but also immunologic, metabolic, toxicological cofactors can be involved. Delay in diagnosis is frequent and may not influence the prognosis, but does not allow conservative therapy. Prognosis depends mainly on pathologic cofactors that require detection and appropriate treatment in order to prevent complications and recurrences.

[Progression from a routine examination to a study. Having come this far, what should be done from now? A thrombosis risk factor study].

We were able to carry out a study of deep venous thrombosis (DVT) with the cooperation of clinicians. I herein describe a part of the study that I have conducted. Japanese patients with DVT were investigated regarding their incidences of antithrombin III (AT-III), protein C (PC), and protein S (PS) deficiencies, and the results were compared with those of normal subjects. We confirmed that the Japanese population has a high frequency of PC and PS deficiencies. Furthermore, we recommend that PS activity should be measured for the screening of thrombosis since type II deficiency accounted for approximately 50% of PS deficiency cases in both patients and the normal group in Japanese. We evaluated the reactivity of thrombin to TM by determining the TM-bound thrombin (TMBTh) to total thrombin generation (t-Th) ratio (TMBT ratio). We also examined whether a decreased TMBT ratio is associated with an increased risk of thrombosis. The TMBT ratio (TMBTh/t-Th) was significantly lower in patients with DVT than in control subjects. These results suggest that it is possible to evaluate the reactivity of thrombin to TM by determining the TMBT ratio, and this ratio may be a predictor of deep vein thrombosis. However, we have yet to investigate the causal mechanism.